U.S. patent application number 17/018888 was filed with the patent office on 2021-03-11 for polymer formulations for nasolacrimal stimulation.
The applicant listed for this patent is Oculeve, Inc.. Invention is credited to F. Richard Christ, Marie Dvorak Christ, Anand Doraiswamy, Amitava Gupta, James Donald Loudin, Christopher William Stivers, John L. Wardle.
Application Number | 20210069496 17/018888 |
Document ID | / |
Family ID | 1000005222921 |
Filed Date | 2021-03-11 |
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United States Patent
Application |
20210069496 |
Kind Code |
A1 |
Loudin; James Donald ; et
al. |
March 11, 2021 |
POLYMER FORMULATIONS FOR NASOLACRIMAL STIMULATION
Abstract
Described herein are polymer formulations for facilitating
electrical stimulation of nasal or sinus tissue. The polymer
formulations may be hydrogels that are prepared by a UV
cross-linking process. The hydrogels may be included as a component
of nasal stimulator devices that electrically stimulate the
lacrimal gland to improve tear production and treat dry eye.
Additionally, devices and methods for manufacturing the nasal
stimulators, including shaping of the hydrogel, are described
herein.
Inventors: |
Loudin; James Donald;
(Alhambra, CA) ; Gupta; Amitava; (Roanoke, VA)
; Wardle; John L.; (San Clemente, CA) ; Stivers;
Christopher William; (San Francisco, CA) ;
Doraiswamy; Anand; (San Francisco, CA) ; Christ;
Marie Dvorak; (Laguna Beach, CA) ; Christ; F.
Richard; (Laguna Beach, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Oculeve, Inc. |
San Francisco |
CA |
US |
|
|
Family ID: |
1000005222921 |
Appl. No.: |
17/018888 |
Filed: |
September 11, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15904036 |
Feb 23, 2018 |
10799696 |
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17018888 |
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15700935 |
Sep 11, 2017 |
9956397 |
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15904036 |
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14630471 |
Feb 24, 2015 |
9770583 |
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15700935 |
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62067350 |
Oct 22, 2014 |
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62035221 |
Aug 8, 2014 |
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62027139 |
Jul 21, 2014 |
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61944340 |
Feb 25, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/0456 20130101;
A61N 1/36014 20130101; C08F 220/54 20130101; Y10T 29/49885
20150115; Y10T 29/49826 20150115; C08F 230/08 20130101; A61N 1/0496
20130101; A61N 1/0546 20130101; H01B 1/125 20130101; C08F 220/20
20130101 |
International
Class: |
A61N 1/05 20060101
A61N001/05; H01B 1/12 20060101 H01B001/12; A61N 1/04 20060101
A61N001/04; C08F 220/54 20060101 C08F220/54; C08F 230/08 20060101
C08F230/08; C08F 220/20 20060101 C08F220/20 |
Claims
1-101. (canceled)
102. A method of manufacturing a hydrogel electrode of a nasal
stimulator device, the method comprising: dispensing a hydrogel
mixture into a mold defining the hydrogel electrode of the nasal
stimulator device; curing the hydrogel mixture; and removing the
cured hydrogel mixture from the mold, the cured hydrogel mixture
forming the hydrogel electrode of the nasal stimulator device.
103. The method of claim 102, wherein the hydrogel mixture
comprises a mixture of: glycerol monomethacrylate; trimethylol
propane trimethacrylate; dimethylacrylamide; N-vinylpyrrolidone;
2,4,6-trimethylbenzoyl-diphenylphosphine oxide; and methanol.
104. The method of claim 103, wherein the hydrogel mixture further
comprises a surfactant.
105. The method of claim 103, wherein the hydrogel mixture further
comprises propylene glycol.
106. The method of claim 103, wherein the hydrogel mixture further
comprises 3-[tris(trimethylsiloxy)silyl]propyl methacrylate.
107. The method of claim 102, further comprising: modifying a
surface of the hydrogel electrode to cause the surface to increase
in hydrophilic properties.
108. The method of claim 107, wherein the modifying includes
treating the surface with a low pressure plasma material.
109. The method of claim 108, wherein the plasma material includes
one or more of air, oxygen, and water vapor.
110. The method of claim 107, wherein the modifying includes
depositing a hydrophilic polymer on the surface of the hydrogel
electrode.
111. The method of claim 102, wherein the hydrogel electrode is
configured to provide an electrical connection between an electrode
of the nasal stimulator device and tissue of a user.
112. The method of claim 102, wherein the hydrogel electrode is
biocompatible.
113. A method of manufacturing a stimulation probe of a nasal
stimulator device, the method comprising: applying a hydrogel
mixture to a stimulation electrode of the nasal stimulator device;
and curing the hydrogel mixture to form a hydrogel electrode for
providing an electrical connection between the stimulation
electrode and tissue of a user.
114. The method of claim 113, wherein the hydrogel mixture
comprises a mixture of: glycerol monomethacrylate; trimethylol
propane trimethacrylate; dimethylacrylamide; N-vinylpyrrolidone;
2,4,6-trimethylbenzoyl-diphenylphosphine oxide; and methanol.
115. The method of claim 114, wherein the hydrogel mixture further
comprises a surfactant.
116. The method of claim 114, wherein the hydrogel mixture further
comprises propylene glycol.
117. The method of claim 114, wherein the hydrogel mixture further
comprises 3-[tris(trimethylsiloxy)silyl]propyl methacrylate.
118. The method of claim 113, further comprising: modifying a
surface of the hydrogel electrode to cause the surface to increase
in hydrophilic properties.
119. The method of claim 118, wherein the modifying includes
treating the surface with a low pressure plasma material.
120. The method of claim 118, wherein the modifying includes
depositing a hydrophilic polymer on the surface of the hydrogel
electrode.
121. The method of claim 113, wherein the hydrogel electrode is
biocompatible.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/904,036 filed on Feb. 23, 2018, which is a continuation of
U.S. application Ser. No. 15/700,935, filed on Sep. 11, 2017, which
issued as U.S. Pat. No. 9,956,397 on May 1, 2018, which is a
continuation of U.S. application Ser. No. 14/630,471, filed on Feb.
24, 2015, which issued as U.S. Pat. No. 9,770,583 on Sep. 26, 2017,
which claims priority to U.S. Provisional Application No.
61/944,340, filed on Feb. 25, 2014, U.S. Provisional Application
No. 62/027,139, filed on Jul. 21, 2014, U.S. Provisional
Application No. 62/035,221, filed on Aug. 8, 2014, and U.S.
Provisional Application No. 62/067,350, filed on Oct. 22, 2014.
Each of the aforementioned disclosures is hereby incorporated by
reference in its entirety.
FIELD
[0002] Described herein are polymer formulations that provide
electrical contact between an electrode and a nasal or sinus
tissue. Specifically, hydrogel formulations that are cross-linked
using UV radiation are described. Methods of manufacturing the
hydrogels and methods of treating dry eye with nasal stimulator
devices including the hydrogels are also described.
BACKGROUND
[0003] Dry eye disease is a major eye condition throughout the
world for which no permanent cure is currently available. For
example, it has been estimated that the current average annual cost
of treating dry eye disease amounts to $850 per person (Yu, J.,
Andre, C. V., and Fairchild, C. J. "The economic burden of dry eye
disease in the United States: a decision tree analysis." Cornea 30
4 (2011): 379-387). Epidemiological estimates of frequency of
incidence of dry eye disease vary widely, depending on the symptoms
being monitored. For example, Friedman reports that the incidence
of dry eye disease ranges from 5% to 35% globally (Friedman, N.
"Impact of dry eye disease and impact on quality of life." Current
Opinion in Ophthalmology 21 (2010): 310-316).
[0004] Current treatments include the use of lubricants (e.g.,
hydroxymethyl and sodium carboxypropyl cellulose, generally known
as artificial tears), anti-inflammatory therapies (e.g.,
corticosteroids and immunomodulators such as cyclosporin), tear
retention therapies (e.g., punctal plugs), and treatment of
underlying causes such as meibomian gland dysfunction, lid
abnormalities, etc. These treatments have been shown to have a mild
to moderate improvement in the quality of life of the patient. For
example, the Lacrisert.RTM. ophthalmic insert (Aton Phama,
Lawrenceville, N.J.), a hydroxypropyl cellulose ophthalmic insert
placed in the inferior eyelid cul-de-sac, was shown to have a 21%
improvement in ocular surface disease index scores by McDonald, et
al. (McDonald, M. B., D'Aversa, Perry H. D., et al. "Hydroxypropyl
cellulose ophthalmic inserts (Lacrisert) reduce the signs and
symptoms of dry eye syndrome." Trans Am Ophthalmol Soc 107 (2009):
214-222). However, these treatments often require multiple
administrations per day, and typically do not prevent long term
damage to the ocular surface, often caused by the chemical being
administered. For example, it is known that preservatives (e.g.,
benzalkonium chloride) can cause damage to the ocular surface and
cause irritation.
[0005] Accordingly, the development of alternative treatments for
dry eye syndrome would be useful. In particular, treatments that do
not involve long term administration of drug therapy would be
beneficial. Treatments with simplified administration regimens
would further be desirable.
SUMMARY
[0006] Described herein are polymer formulations for facilitating
electrical stimulation of nasal or sinus tissue. The polymer
formulations may form hydrogels that are prepared by a
cross-linking process using UV or visible light. In some
applications the hydrogels may be included as a component of
devices (referred to here and throughout as nasal stimulator
devices or nasostimulator devices) that electrically stimulate the
lacrimal gland via a nasal or sinus afferent nerve in patients
suffering from dry eye to improve tear production. The nasal
stimulators may be used to treat dry eye of varying etiology. For
example, they may be used to treat dry eye due to age, hormonal
imbalances, side effects of medication, and medical conditions such
as Sjogren's syndrome, lupus, scleroderma, thyroid disorders,
etc.
[0007] Generally, the polymer formulations may form electrically
conductive hydrogels comprised of various monomers. The monomers
may be the same or different. The electrically conductive hydrogel
formulations may include a first monomer; a second monomer; and a
photoinitiator. The use of an acrylate monomer, a silane monomer,
an acrylic terminated silane monomer, and/or an acrylic terminated
siloxane monomer as the first monomer or sole monomer component of
the formulation may be beneficial. The electrically conductive
hydrogel will typically have one or more characteristics that adapt
it for use with a nasal stimulator device. In some instances, the
electrically conductive hydrogel is a hydrogel with high water
content, as further described below. As used herein and throughout,
the terms "formulation," "polymer formulation," "hydrogel
formulation," "electrically conductive hydrogel formulation,"
"hydrogel," and "electrically conductive hydrogel" can refer to
formulations comprising monomers and mixtures of monomers, before
or after they have been cured, depending on the context of how the
term is used. It is understood that either the uncured or cured
formulations comprise monomers or a mixture of monomers.
[0008] Processes for producing electrically conductive hydrogels
are also described herein. The processes may generally include the
steps of mixing a first monomer, a second monomer, and a
photoinitiator to prepare a formulation, where the first monomer is
an acrylate monomer; and irradiating the formulation with UV
radiation to cross-link the formulation. The formulation may be
cross-linked by covalent bonds or ionic bonds to form the
hydrogel.
[0009] Methods for manufacturing the nasal stimulator devices,
including shaping of the conductive hydrogel, e.g., to form a bulge
that may enhance contact of the hydrogel to nasal mucosa, and
attaching the tip assembly with or without the shaped hydrogel to a
base unit of the nasal stimulator devices, are also described
herein. The methods for shaping the hydrogel are further described
below and may comprise dipping the tip assembly into the hydrogel,
using the tip assembly to scoop hydrogel therein, molding or
casting the hydrogel, or dispensing the hydrogel into the tip
assembly through a window disposed therethrough. The tip assemblies
comprising the shaped hydrogel may be stored in a dispensing
cassette for later attachment to a base unit of the nasal
stimulator device, as further described below.
[0010] In addition, described herein are methods for stimulating
the nasal cavity or the lacrimal gland comprising placing an arm of
a nasal stimulator device against a nasal or a sinus tissue, the
arm having a distal end and an electrically conductive hydrogel
disposed at the distal end; and activating the nasal stimulator
device to provide electrical stimulation to the nasal or the sinus
tissue. The electrically conductive hydrogel is typically used to
facilitate an electrical connection between the nasal stimulator
device and the nasal or the sinus tissue. These methods may be used
to treat dry eye.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 depicts an exemplary nasal stimulator device having
an adjustable pair of stimulator electrodes.
[0012] FIG. 2 depicts a top view of the disposable component of
another exemplary nasal stimulator device including a pair of
spring-like electrodes substantially enclosed by an opaque
sleeve.
[0013] FIGS. 3A-3C depict exemplary configurations of the
electrically conductive polymer provided in the disposable
component of a nasal stimulator device. FIG. 3A shows a perspective
view of the stimulator electrode surrounded by an opaque polymeric
sleeve. FIG. 3B is a cross-sectional view of the stimulator
electrode in FIG. 3A showing an electrically conductive polymer
disposed within the tip portion. FIG. 3B depicts a stylized view of
the stimulator electrode in FIG. 3A where the conductive polymer
forms a shell around the distal end of the polymeric sleeve.
[0014] FIG. 4 depicts an exemplary disposable mold for use in
forming the hydrogel component of a nasal stimulator device.
[0015] FIG. 5 illustrates an exemplary assembly process for the
disposable component.
[0016] FIG. 6 depicts the chemical structure of exemplary acrylic
terminated silane and siloxane monomers.
[0017] FIG. 7 depicts the proposed morphology of the SB5 hydrogel
formulation cured to form the electrical contact at the tip of a
nasal stimulator device.
[0018] FIGS. 8A-8C depict exemplary methods for shaping the
hydrogel included in the nasal stimulator device tip. FIG. 8A
depicts a dipping method for hydrogel shaping. FIG. 8B illustrates
a scooping method for hydrogel shaping. FIG. 8C shows a hydrogel
tip in which part of the tip has been masked during spraying of an
insulator to provide a conductive portion.
[0019] FIGS. 9A-9I depict exemplary methods for shaping the
hydrogel by molding and then cutting.
[0020] FIGS. 10A-10C depict exemplary dispensing methods and
dispensing devices for shaping the hydrogel.
[0021] FIGS. 11A-11C depict exemplary structures and methods that
may be used to help control dispensing of the hydrogel.
[0022] FIGS. 12A-12D depict an exemplary mold and casting method
for shaping the hydrogel.
[0023] FIG. 13 shows an exemplary thin walled tip capable holding
larger volumes of hydrogel.
[0024] FIGS. 14A-14D show an exemplary tip assembly structure and
method of attaching the structure to a prong of a nasal stimulator
device.
[0025] FIGS. 15A-15C show an exemplary method where a hydrogel
preform is included in the tip assembly and then hydrated.
[0026] FIGS. 16A-16D depict exemplary tip assembly structures and
methods of use that include a hinge.
[0027] FIGS. 17A-17E depict an exemplary dispensing cassette and
method for manufacturing the tip assemblies.
[0028] FIGS. 18A-18D illustrate an exemplary method of attaching
tip assemblies to a base unit using the dispensing cassette of
FIGS. 17A-17E.
[0029] FIGS. 19A-19C show an exemplary tool and method for removing
tip assemblies from the base unit.
[0030] FIGS. 20A-20B show additional exemplary tip assembly
structures and assembly methods thereof.
[0031] FIGS. 21A-21B show DMA and NVP monomer extraction rates for
the SB1 hydrogel.
[0032] FIGS. 22A-22B show NVP monomer and methanol extraction rates
for the SB2 hydrogel.
[0033] FIGS. 23A-23B provide data relating to hydration of the SB1
and SB2 hydrogels as a function of electrical resistance.
[0034] FIGS. 24A-24B provide data relating to the hydration of the
SB2 and SB3 hydrogels as a function of electrical resistance.
[0035] FIG. 25 provides data relating to the hydration of the SB4A
and SB4B hydrogels as a function of electrical resistance.
[0036] FIGS. 26A-26B provide data relating to expansion of the SB2
and SB3 hydrogels due to hydration.
[0037] FIGS. 27A-27B provide data relating to expansion of the SB4A
and SB4B hydrogels due to hydration.
[0038] FIGS. 28A-28C show DMA and NVP monomer, and methanol
extraction rates for the SB5 hydrogel.
[0039] FIG. 29 provides data relating to the hydration of the SB5
hydrogel as a function of electrical resistance.
[0040] FIGS. 30A-30C provide data relating to expansion of the SB5
hydrogel due to hydration.
DETAILED DESCRIPTION
[0041] The polymer formulations described herein are generally
hydrogels that may be used to facilitate an electrical connection
between an electrode of a nasal stimulator device and nasal or
sinus tissue, as mentioned above. Accordingly, the hydrogels are
biocompatible and formed to be non-irritating and non-abrasive to
nasal and sinus tissue. The hydrogels are generally also formed so
that they do not break or shatter during insertion or use, and have
moderate adhesion to nasal or sinus tissue in order to minimize
contact resistance, heating, and heat damage to the tissue it
contacts. The hydrogels may be prepared by cross-linking of various
monomers using UV or visible light. The nasal stimulator device may
include a disposable component and a reusable component. The
disposable component may generally include a pair of stimulator
electrodes and the electrically conductive hydrogel, and the
reusable component a source of electrical energy for the stimulator
electrodes. However, in some instances the nasal stimulator device
can be made to be completely disposable.
Electrically Conductive Hydrogel Formulations
[0042] The electrically conductive hydrogels ("conductive
hydrogels") may comprise any monomer that is capable of providing a
formulation suitable for use with nasal or sinus tissue, and
suitable to facilitate an electrical connection between a nasal
stimulator device, e.g., a hand-held nasal stimulator device, and
nasal or sinus tissue. The formulation is typically prepared by UV
cross-linking of the monomers, as further described below. In some
variations, the formulations provide electrically conductive
acrylate/methacrylate/vinyl hydrogels. In other variations, the
formulations provide electrically conductive silicone-acrylate
hydrogels.
[0043] In one variation, the conductive hydrogel formulation may
include a first monomer; a second monomer; and a photoinitiator,
where the first monomer is an acrylate monomer. Here the acrylate
monomer may be a monofunctional monomer, a difunctional monomer, a
trifunctional monomer, or a precursor or a derivative thereof.
[0044] Examples of monofunctional monomers that may be included in
the formulations include without limitation, acrylic acid, butyl
acrylate, butyl methacrylate, 2-chloroethyl vinyl ether, ethyl
acrylate, 2-ethylhexyl acrylate, furfuryl acrylate, glycerol
monomethacrylate, hydroxyethyl methacrylate, methacrylic acid,
methoxy polyethylene glycol dimethacrylate, methoxy polyethylene
glycol monoacrylate, and aminoethyl methacrylate.
[0045] The difunctional monomers that may be used in the
formulations include, but are not limited to, diethylene glycol
diacrylate, ethylene glycol dimethacrylate, neopenyl glycol
diacrylate, polyethylene glycol diacrylate, polyethylene glycol
di-methacrylate, triethylene glycol diacrylate, and N,N'
dimethylene bisacrylamide.
[0046] With respect to the trifunctional monomer, examples include
without limitation, pentaerythritol triacrylate, propxylated glycol
triacrylate, trimethylpropane triacrylate, and trimethylol propane
trimethacrylate.
[0047] The first monomer and the second monomer may or may not be
the same type of monomer. Examples of second monomers include, but
are not limited to, dimethylacrylamide, glycidyl methacrylate,
N-vinylpyrrolidone, and 1,4-butanediol diacrylate.
[0048] Silane or siloxane monomers may also be used to form an
electrically conductive hydrogel. Suitable siloxane monomers
typically comprise a --O--Si group. In one variation, silane
methacrylate monomers are included in the conductive hydrogel
formulations as the first and/or second monomer. For example,
methacryloxypropyltris (trimethylsiloxy) silane,
methacryloxymethyltris (trimethylsiloxy) silane,
methacrylodxypropylbis (trimethylsioloxy) silanol,
3-methoxypropylbis(trimethylsiloxy) methyl silane,
methacryloxypentamethyldisiloxane, methacryloxypropyltrimethoxy
silane, and methacryloxypropyltris (methoxyethoxy) silane monomers
may be used. In further variations, acrylic terminated silane and
siloxane monomers, e.g., as shown in FIG. 6 may be used. These
acrylic terminated silane and siloxane monomers include, but are
not limited to, trimethyl silyl methacrylate, 2 (trimethylsilyloxy)
ethyl methacrylate, 3-(trimethyoxysilyl)propyl methacrylate, and
(3-methacryloyloxypropyl) tris (trimethylsiloxy)silane. In some
instances, it may be beneficial to include 3-methacryloxyproplyl
tris (trimethyl siloxy) silane in the hydrogels. Vinyl substituted
silane monomers may also be used in the hydrogel formulations. Here
the silane monomer may be one that comprises a --SiR group, where R
may be hydrogen, or a methyl or an alkyl group.
[0049] Hydrogels containing siloxane monomers may retain the water
they absorb over a longer exposure to air, and thus, retain their
electrical conductivity for a longer period of time. The mole
fraction of siloxane groups in the silicone hydrogels may range
from about 5% to about 20%. When a silane group is employed, the
mole fraction of silane groups in the hydrogels may range from
about 5% to about 20%.
[0050] The conductive hydrogels may be formed by a UV cross-linking
process. In this instance, a photoinitiator is generally included
in the formulation. Photoinitiators may be any chemical compound
that decomposes into free radicals when exposed to light, e.g., UV
radiation having a wavelength in the range of about 350 nm to about
450 nm. The free radicals initiate polymerization to form
cross-linked hydrogels. In one variation, the photoinitiator
initiates ring opening polymerization. In another variation, the
photoinitiator initiates cationic polymerization. In a further
variation, the photoinitiator initiates polymerization by a
thiol-ene reaction.
[0051] Any suitable photoinitiator may be employed in the
formulations described herein. For example, the photoinitiator may
be selected from the group consisting of acylphosphine oxides
(APOs), bisacylphosphine oxides (BAPOs),
2,2-dimethoxy-1,2-diphenylethan-1-one (Igracure.RTM.
photoinitiator), benzoin ethers, benzyl ketals,
alpha-dialkoxyacetophenones, alpha-hydroxyalkylphenones,
alpha-amino alkylphenones, benzophenones, thioxanthones, and
combinations and derivatives thereof. In some instances, it may be
useful to include an acylphosphine oxide or bisacylphospine oxide
photoinitiator in the formulation.
[0052] The acylphosphine oxide photoinitiators that may be used
include without limitation, 2,4,6-trimethylbenzoyl-diphenylphospine
oxide (TMDPO); benzoyl-diphenylphosphine oxide (BDPO);
2,4,6-trimethylbenzoyl-methoxy-phenylphosphine oxide (TMMPO);
phthaloyl-bis(diphenylphosphine oxide (PBDPO));
tetrafluoroterephthanoyl-bis(diphenylphosphine oxide) (TFBDPO);
2,6-difluoro benzoyl-diphenylphospine oxide (DFDPO);
(1-naphthoyl)diphenylphosphine oxide (NDPO); and combinations
thereof. In one variation, 2,4,6-trimethylbenzoyl-diphenylphospine
oxide (TMDPO) is a useful photoinitiator.
[0053] The bisacylphosphine oxide photoinitiators that may be used
include without limitation,
bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (BTMPO);
bis(2,6-dimethoxybenzoyl)-2,4,4-trimethyl-pentylphosphine oxide;
1-hydroxy-cyclohexyl-phenyl-ketone; and combinations thereof.
[0054] The conductive hydrogels described herein may further
include a suitable diluent. Suitable diluents may be glycerin,
isopropanol, polyethylene glycol, water, methanol, and combinations
thereof. Table 1 shows an exemplary list of monomers,
photoinitiators (e.g., UV initiators), and diluents that may be
used to make the conductive hydrogels.
TABLE-US-00001 TABLE 1 Exemplary list of formulation monomers,
diluents, and UV initiators. Silane and Monofunctional Difunctional
Trifunctional Siloxane Monomers Monomers Monomers Monomers UV
Initiators Diluents Acrylic acid Ethylene glycol Pentaerythritol
Trimethyl silyl Irgacure 189 Water dimethacrylate triacrylate
methacrylate (Ciba/BASF) Methacrylic acid Polyethylene Trimethyl-
2(trimethylsilyloxy) Irgacure 819 Isopropanol glycol propane Ethyl
methacrylate (Ciba/BASF) diacrylate (200- triamylate 1500) Methoxy
Neopentyl Propoxylated 3(trimethoxysilyl) Irgacure 1173
Polyethylene polyethylene glycol glycol glycol propyl methacrylate
(Ciba/BASF) glycol monoacrylate (300- diacrylate triamylate 550)
Methoxy Diethylene Trimethylol 3(methacryloyloxy Lucirin TPO
Glycerin polyethylene glycol glycol Propane propyl) tris (BASF)
dimethacylate diacrylate trimethacrylate (trimethylsiloxy silane)
Hydroxyethyl Triethylene Methanol methacrylate glycol diacrylate
Furfuryl Acrylate N,N' dimethylene bisacrylamide Glyceryl
Polyethylene monomethacrylate glycol di-methacrylate
[0055] In some variations, the monofunctional monomers are selected
from Table 1 and comprise no more than 80% and no less than 30%
moles/mole of the formulation prior to addition of diluents. In
other variations, the difunctional monomers are selected from Table
1 and comprise no more than 25% and no less than 5% moles/mole of
the formulation prior to the addition of diluents. In further
variations, the trifunctional monomers are selected from Table 1
and comprise about 0.0 to about 5.0 moles/100 moles of the
formulation prior to the addition of diluents.
[0056] The conductive hydrogels will generally be formed to have
one or more characteristics that adapt it for use with a nasal
stimulator device. For example, characteristics such as electrical
resistivity, maximum hydration level, tensile strength (elongation
break), Young's modulus, glass transition temperature, and
cross-link density, may be adjusted to adapt the conductive
hydrogel for use with a nasal stimulator device.
[0057] The electrical resistivity of the conductive hydrogel may
range from about 50 to about 2,000 Ohmcm, or from about 150 to
about 800 Ohmcm. In one variation, the electrical resistivity
ranges from about 400 to about 800 Ohmcm. In another variation, the
electrical resistivity ranges from about 200 to about 600 Ohmcm. In
a further variation, the electrical resistivity ranges from about
150 to about 500 Ohmcm. Alternatively, the electrical resistivity
may range from about 550 to about 600 Ohmcm.
[0058] With respect to other characteristics of the conductive
hydrogel, the maximum hydration level may range from about 35% to
about 80% by weight, and the tensile strength (elongation at break)
may range from about 35% and 150%, or from about 35% to about 100%,
at 30% relative humidity. Here hydration level is defined as
(W.sub.hydrated polymer-W.sub.dry polymer)/W.sub.hydrated polymer.
Young's modulus ranges of the conductive hydrogel may range from
about 0.1 to about 1.5 MPa, or from about 0.1 to about 1.0 MPa. The
glass transition temperature of the conductive hydrogel may range
from about 5 to about 65 degrees Celsius in the dry state.
Furthermore, the cross-link density may range from about 0.01 to
about 0.10 moles/mole.
[0059] The conductive hydrogel formulations may contain fillers to
improve one or more of the following: mechanical properties,
cosmetic appearance, electrical properties, and cost. Suitable
fillers may include without limitation, silica, alumina, titanium
dioxide, polyethylene microspheres, carbon black, nanofibers,
nanoparticles, and combinations thereof.
[0060] The conductive hydrogel formulations may be a homogenous
material or they may comprise a multiphase blend or a block
copolymer with relatively hydrophobic and relatively hydrophilic
domains that have undergone a microphase separation.
[0061] Additionally, the conductive hydrogel formulations may
contain additives that are either soluble or present in a dispersed
form in the polymer material. These additives may include
hydrophilic molecules, cage molecular structures, surface modifying
agents, or amphiphilic molecules. Exemplary amphiphilic molecules
include without limitation, cellulose, dextran, hydroxypropyl
cellulose, hydroxymethyl cellulose, hyaluronic acid, sodium
hyaluronate, chitin, chitosan, crown ether derivatives, and
combinations thereof.
[0062] Conductive hydrogel formulations having the following
characteristics may be useful in facilitating electrical
communication between a nasal stimulator device and nasal or sinus
tissue: [0063] Electrical resistivity ranging from 200-800 Ohmcm,
elongation at break greater than 50% in tensile mode, and hydration
level in the range of 25-80% (hydration level being expressed as
the equilibrium swelling ratio, W.sub.h/W.sub.G.times.100, where
W.sub.h is the mass of water at equilibrium at a particular
temperature, and W.sub.G is the weight of the hydrated gel measured
under the same conditions); [0064] Electrical resistivity at the
fully hydrated state ranging from 300 to 500 Ohmcm; [0065]
Equilibrium swelling ratio ranging from 35-65%; [0066] Hydration
level that does not change by more than approximately 10% (or 5.0
to 30 g if comparing hydrogel weight before and after hydration),
over 15 hours of continuous exposure to indoor air at 25 degrees
Celsius, with a relative humidity not less than 30%; [0067] Young's
modulus ranging from 0.10 to 10 MPa in the fully hydrated state,
and a glass transition temperature of the dry gel ranging from 5 to
65 degrees Celsius; or [0068] Cross-link density ranging from 0.01
to 0.10 moles/mole.
[0069] Some variations of the conductive materials may comprise
polyethylene or polypropylene polymers filled with carbon black or
metal particles. Other variations may include conducting polymers
such as poly-phenylene sulfide, poly-aniline, or poly-pyrrole.
Ionically conducting variations such as hydrophilic, cross-linked
polymer networks are also contemplated. However, in some instances
the conductive hydrogel may be neutral and comprise hydrophobic
segments or domains in a hydrophilic network. In yet further
variations, the conductive hydrogel may comprise ionic pendant
groups, some of which provide ionic or electrostatic cross-linking.
A conductive hydrogel that is a biocompatible, hydrophilic,
cross-linked network comprising hydrophobic segments, and which has
a glass transition temperature in the range 5 to 65 degrees
Celsius, and an elongation at break in the range of 50% to 150% may
be useful.
[0070] In yet further variations, it may be beneficial for the
conductive hydrogels to have a high water content, e.g., a water
content of 60% or greater, as calculated by the following formula:
percent water=(W.sub.hydrated gel-W.sub.dry gel)/(W.sub.hydrated
gel).times.100, where W is weight. In some variations, the water
content may range from about 60% to about 99%, from about 60% to
about 95%, from about 60% to about 90%, from about 60% to about
85%, from about 60% to about 80%, from about 60% to about 75%, from
about 60% to about 70%, or from about 60% to about 70%. In general,
the lower limit is the amount of water needed to be absorbed so
that the hydrogel maintains a high water content after several
hours of exposure to air at room temperature and moderate levels of
relative humidity. The value for the upper limit of water content
may be influenced by the need to have mechanical robustness,
including a tensile modulus higher than about 0.1 MPa and an
elongation break greater than 50%.
[0071] Exemplary conductive hydrogels having high water content may
comprise cross-linked networks that include monomers such as
acrylamide, methacrylamide, dimethylacrylamide, or combinations
thereof. In one variation, the high water content hydrogel includes
poly-dimethylacrylamide cross-linked by potassium persulfate.
[0072] In another variation, the high water content hydrogel may
comprise an ionic co-monomer including, but not limited to, sodium
acrylate, zinc arylate, calcium acrylate, or combinations thereof.
The ionic co-monomer may be used at a concentration ranging from
zero to about 20 mole percent. Hydrogels using an ionic co-monomer
may have a percent water content of 99% or more.
[0073] Hydrogels having a high water content generally have an
elastic modulus ranging from about 0.001 to 0.01 MPa. When employed
with the nasal stimulator devices referred to herein, the hydrogels
may require a higher level of cross-linking so that the minimum
elastic modulus is about 0.1 MPa. The additional cross-linking may
be provided by adding N,N'diethyl bis-acrylamide co-monomer to the
hydrogel formulation. The N,N'diethyl bis-acrylamide co-monomer may
be added in an amount ranging from about 0.5% to about 2.0%, or
from about 0.5% to about 1.0% by weight of the formulation.
Exemplary conductive hydrogel formulations with high water conduct
are provided below in Table 2.
TABLE-US-00002 TABLE 2 Exemplary Conductive Hydrogel Formulations
with High Water Content MONOMER CONCENTRATION Function N,N'
Dimethyl acrylamide 50-90% Monomer and cross-linker N,N' Dimethyl
0.5-2.0% Cross-linker bisacrylamide Sodium Arrylate 0-10% Monomer
Zinc acrylate 0-10% Monomer Polyethylene glycol 0-10% Cross-linker
diacrylate Cumyl hydroperoxide 0-1% Initiator Potassium persulfate
0-1% Initiator
[0074] In some variations, it may be useful to include hydrophilic
groups into the conductive hydrogels so that the hydrogels form a
relatively strong complex with water molecules, thereby increasing
the activation energy of the dehydration process in the molecular
structure of the hydrogel network and reducing the drying out (or
dry out) rate of the hydrogels. For example, polysaccharides may be
included in the hydrogels as a hydrophilic additive since they are
biocompatible, strongly bind water, and can be chemically
immobilized on the hydrogel network. The polysaccharides that may
be used include, but are not limited to, dextran sulfate,
hyaluronic acid, sodium hyaluronate, hydroxymethyl cellulose,
chitosan, sodium alginate, and combinations thereof. When a
polysaccharide additive is employed, it may be included in the
hydrogels in an amount ranging from about 0.5% to about 20%, from
about 0.5% to about 15%, from about 0.5% to about 10%, or from
about 0.5% to about 5%, by weight of the formulation. The
polysaccharide additive may be added to the monomer formulation or
it may be incorporated into the network during hydration.
[0075] The drying out rate of the hydrogel can also be
substantially reduced by including a hydrating agent or a hydrating
medium in the hydrogel formulation. For example, propylene glycol
and polymers thereof can be included as a hydrating agent.
Additionally, mixtures of propylene glycol and water can be used as
a hydrating medium. The inclusion of a propylene glycol and water
mixture in the hydrogel formulation may result in less water being
present at the hydrogel surface, and thus evaporated from, the
hydrogel surface.
[0076] Propylene glycol and water can be combined in various
amounts or ratios in the hydrating medium. In some variations, the
hydrating mixtures can comprise propylene glycol in an amount
between about 5 to about 85 percent by volume, between about 5 to
about 80 percent by volume, between about 5 to about 75 percent by
volume, between about 5 to about 70 percent by volume, between
about 5 to about 65 percent by volume, between about 5 to about 60
percent by volume, between about 5 to about 55 percent by volume,
between about 5 to about 50 percent by volume, between about 5 to
about 45 percent by volume, between about 5 to about 40 percent by
volume, between about 5 to about 35 percent by volume, between
about 5 to about 30 percent by volume, between about 5 to about 25
percent by volume, between about 5 to about 20 percent by volume,
between about 5 to about 15 percent by volume, or between about 5
to about 10 percent by volume. In other variations, the hydrating
mixtures can comprise propylene glycol in an amount between about
20 to about 50 percent by volume or between about 20 to about 35
percent by volume. In further variations, the hydrating mixtures
can comprise propylene glycol in an amount of about 5 percent by
volume, about 10 percent by volume, about 15 percent by volume,
about 20 percent by volume, about 25 percent by volume, about 30
percent by volume, about 35 percent by volume, about 40 percent by
volume, about 45 percent by volume, about 50 percent by volume,
about 55 percent by volume, about 60 percent by volume, about 65
percent by volume, about 70 percent by volume, about 75 percent by
volume, about 80 percent by volume, or about 85 percent by
volume.
[0077] Water may make up the remainder of the hydrating mixtures,
or in some instances, other components may be included. The
hydrating mixtures can comprise water in an amount between about 15
to about 95 percent by volume. For example, the hydrating mixtures
can comprise water in an amount of about 15 percent by volume,
about 20 percent by volume, about 25 percent by volume, about 30
percent by volume, about 35 percent by volume, about 40 percent by
volume, about 45 percent by volume, about 50 percent by volume,
about 55 percent by volume, about 60 percent by volume, about 65
percent by volume, about 70 percent by volume, about 75 percent by
volume, about 80 percent by volume, about 85 percent by volume,
about 90 percent by volume, or about 95 percent by volume. Instead
of water, saline may also be used, and included in the same amounts
described as for water.
[0078] Exemplary hydrating mixtures may include propylene glycol
and water (or saline) in the following amounts: about 5 percent by
volume propylene glycol and about 95 percent by volume water; about
10 percent by volume propylene glycol and about 90 percent by
volume water; about 15 percent by volume propylene glycol and about
85 percent by volume water; about 20 percent by volume propylene
glycol and about 80 percent by volume water; about 25 percent by
volume propylene glycol and about 75 percent by volume water; about
30 percent by volume propylene glycol and about 70 percent by
volume water; about 35 percent by volume propylene glycol and about
65 percent by volume water; about 40 percent by volume propylene
glycol and about 60 percent by volume water; about 45 percent by
volume propylene glycol and about 55 percent by volume water; about
50 percent by volume propylene glycol and about 50 percent by
volume water; about 55 percent by volume propylene glycol and about
45 percent by volume water; about 60 percent by volume propylene
glycol and about 40 percent by volume water; about 65 percent by
volume propylene glycol and about 35 percent by volume water; about
70 percent by volume propylene glycol and about 30 percent by
volume water; about 75 percent by volume propylene glycol and about
25 percent by volume water; about 80 percent by volume propylene
glycol and about 20 percent by volume water; or about 85 percent by
volume propylene glycol and about 15 percent by volume water. The
exemplary hydrating mediums provided below in Table 3 may be useful
in hydrogels that are employed as electrical contacts in nasal
stimulator devices.
TABLE-US-00003 TABLE 3 Exemplary Hydrating Mediums Hydrating
Hydrating Hydrating Hydrating Component/Amount Medium 1 Medium 2
Medium 3 Medium 4 Propylene Glycol 35 40 45 50 (vol %) Water (vol
%) 65 60 55 50
[0079] The hydrogels described herein generally have a functional
time period and a dry out time period. The functional time period
is typically the period of time during which the hydrogels can be
used without substantial loss of function (e.g., the impedance of
the hydrogel does not rise higher than about 2500 Ohms). The dry
out time period is typically the maximum time period of use of the
hydrogel, where at the end of the period, function, e.g.,
stimulative function, of the hydrogel has substantially decreased.
It would be beneficial to maximize both the functional time period
and dry out time period for the hydrogel tips of the nasal
stimulator devices described herein to extend, e.g., their shelf
life. Table 4 provides the functional time periods, dry out time
periods, and impedances for four exemplary hydrogel tips. All four
hydrogels included the SB5 formulation described in Example 15, but
further included a propylene glycol hydrating medium having
propylene glycol amounts varying from about 35 percent by volume to
about 50 percent by volume.
TABLE-US-00004 TABLE 4 Exemplary Functional Time Periods, Dry Out
Time Periods, and Impedances Hydrogels with Propylene Glycol (PG)
Hydrating Medium 35 vol % PG 40 vol % PG 45 vol % PG 50 vol % PG
Functional Time 14 17.1 22 24.4 Period (hours) Dry Out Time 17.8
22.1 27.1 31.0 Period (hours) Impedance 1150 1300 1670 1600
(ohms)
[0080] By varying the amount or ratio of propylene glycol in the
hydrating medium, Table 4 shows that lifetime of the hydrogel tip
can be tailored to the desired indication. For example, if a nasal
stimulator device is intended for single day use, it may be useful
to include a 35 percent by volume (vol %) propylene glycol
hydrating medium to form the hydrogel tip. The hydrogels, whether
they include a hydrating agent or hydrating medium, or whether they
do not include a hydrating agent or hydrating medium, can be
suitably sized, shaped, molded, etc. to form an electrical contact
of a nasal stimulator device. For example, the hydrogels can be
included as part of a prong of a nasal stimulator device, generally
at the tip of the prong. Although the use of the hydrating mediums
in hydrogel tips for nasal or sinus stimulation has been described,
it should be understood that they can be used in hydrogels for
other applications.
[0081] As stated above, the conductive hydrogels can be included in
the prongs or tips of nasal stimulator devices and used to
facilitate an electrical connection between a nasal stimulator
device and nasal or sinus tissue. Some examples of such nasal
stimulator device prongs or tips are provided in U.S. application
Ser. No. 14/256,915 (U.S. Publication No. 2014/0316485), entitled,
"NASAL STIMULATION DEVICES AND METHODS," filed Apr. 18, 2014, the
contents of which are hereby incorporated by reference in their
entirety (the conductive hydrogels in U.S. application Ser. No.
14/256,915 are referred to as hydrogel electrodes). The nasal
stimulator device may be configured to include a disposable
component that is removably attached to a reusable component or
housing. An exemplary disposable component is shown in FIG. 1. In
that figure, the disposable unit (100) consists of a pair of arms
or prongs (102, 106) that house electrodes (not shown), which are
adjustable in a lateral direction, and which can also be rotated or
swung so as to vary the angle between them. Each electrode is
provided in the form of a metal rod that is encased in a polymeric
sleeve (104). Each sleeve (104) ends in a slot (108, 110), to be
filled with an electrically conducting polymer (e.g., hydrogel)
that forms an electrical contact between the electrode and nasal or
sinus tissue.
[0082] Alternatively, and as illustrated in FIG. 2, the disposable
unit (200) has a pair of arms or prongs (202, 204) that comprise an
opaque polymeric sleeve (206) encasing electrodes (not shown). The
opaque polymeric sleeve may be configured to completely cover the
electrodes or to partially cover the electrodes. In this variation,
the sleeve (206) and the electrodes are made flexible and spring
like. Their flexibility is designed to accommodate variations in
the width of the nose, and the angular orientation preferred by an
individual user. Similar to FIG. 1, an electrically conductive
hydrogel can be disposed at the tip of the prongs (202, 204) to
function as an electrical contact between the electrode and the
nasal or sinus tissue.
[0083] FIGS. 3A-3C provide exemplary configurations of the
conductive hydrogel when employed with a nasal stimulation device.
FIG. 3 shows the polymeric sleeve (300) as an opaque tube, which
surrounds the supporting electrode inside. In this variation, the
sleeve (300) ends in a slot that is filled with a conductive
polymer that provides an electrical connection between the
electrode and nasal or sinus tissue. As depicted in the
cross-sectional view of FIG. 3B, the polymer (302) fills the slot
(304) and forms a slightly protruding cylindrical surface for
optimum contact with nasal tissue. It may be beneficial for this
polymer to be squeezable, so that it can conform to the contours of
the nasal cavity, which is lined with a mucous membrane of squamous
epithelium, which tissue then transitions to become columnar
respiratory epithelium. The cavity provides drainage for the
sinuses and the nasolacrimal duct, and therefore presents a highly
humid and moist environment. (Anatomy of the human nose,
Wikipedia). In the variation shown in FIG. 3B, the conductive
polymer forms a shell (306) around the end of the sleeve (300),
filling the slot and extending down the sleeve to contact the
electrode.
Process for Making the Electrically Conductive Hydrogels
[0084] The process for producing the electrically conductive
hydrogels described herein generally comprise the steps of: mixing
a first monomer, a second monomer, and a photoinitiator to prepare
a formulation, wherein the first monomer is an acrylate monomer;
and irradiating the formulation with UV radiation to cross-link the
formulation. The monomers may be ones provided above, e.g., as
listed in Table 1. In some variations, the conductive hydrogel is
cross-linked by covalent bonds. In other variations, the hydrogel
is cross-linked by ionic bonds. In hydrogels with hydrophilic and
hydrophobic domains, the hydrophobic domains may form a shell
around a hydrophilic core, forming a core-shell structure. A
hydrogel with a high water content (e.g., 50-70%) with a
hydrophobic shell may dry out more slowly than a hydrogel without a
hydrophobic shell, and therefore may retain its electrical
conductivity for a longer period when left exposed to air in
between uses.
[0085] In some variations, the hydrogel may be surface modified to
develop a relatively more hydrophilic surface in order to further
reduce skin resistance upon contact with nasal tissue. Surface
modification may be desired for hydrogels that have developed a
hydrophobic shell, leading its surface to become hydrophobic. In
this application, a surface is generally deemed to be hydrophobic
if its water contact angle (sessile drop) exceeds 80 degrees, while
it is generally deemed to be hydrophilic if the contact angle is
less than 30 degrees. Surface modification may be achieved in
several ways. One method is to treat the formed hydrogel with a low
pressure plasma, produced by an RF discharge or a microwave
discharge. Suitable plasma materials include air, oxygen, and water
vapor. This method is believed to cause chemical modification of
the molecules on the surface, forming hydroxyl groups that render
the surface hydrophobic. Another method is to deposit a hydrophilic
polymer via plasma polymerization, including plasma assisted
chemical vapor deposition (PACVD), or plasma initiated chemical
vapor deposition (PICVD). Suitable materials to be deposited using
the plasma polymerization method include HEMA or GMA. Yet another
surface modification method, applicable to hydrogels with siloxane
groups on the surface (e.g., hydrogel SB5 described in Examples
15-19 below), includes chemical activation of the surface, for
example, by treating the surface with aqueous sodium hydroxide
(1-10% w/w), washing it to remove unreacted alkali, then reacting
it with a hydroxyl or amino terminated molecule such as
polyethylene glycol. In yet another method, surface modification
may consist of the addition of a surfactant into the hydrogel
formulation that migrates to the surface upon polymerization. A
surfactant is an amphiphilic molecule that exposes a hydrophilic
end at the surface of the hydrogel. Exemplary surfactants include
sodium dodecyl sulfate, salts of polyuronic acid, Triton X-80, etc.
Alternatively, the hydrogel surface may be modified, e.g., to
become more hydrophilic, by including a hydrating medium into the
formulation. Exemplary hydrating mediums are described above.
[0086] The conductive hydrogel formulations may be prepared to cure
to a zero or a low expansion solid that is formulated with diluents
in the same weight fraction as the equilibrium swelling ratio of
the hydrogel when fully cured. The weight ratio of diluents to the
monomer and photoinitiator mix may be from about 35% to about 70%.
Exemplary diluents that may be employed are listed in Table 1.
These diluents are water soluble, biocompatible, and have a
viscosity less than 100 CST at 25 degrees Celsius.
[0087] The curing process may be caused by any suitable wavelength
of light. In some variations, the curing process is caused by
irradiation with UV light in the wavelength range of about 350 nm
to about 450 nm, and is catalyzed by one or more photoinitiators
selected from Table 1. Other photoinitiators, also as described
above may be used. For example, acylphosphine oxides and
bisacylphosphine oxides that are biocompatible, and which absorb
long wavelength ultraviolet radiation may be used.
[0088] Table 5 provides an exemplary list of conductive hydrogel
formulations that were cured by irradiation with UV light at a
wavelength range of 300 nm to 480 nm, e.g., 350 nm to 450 nm, at a
temperature ranging from 10 to 65 degrees Celsius, preferably 25 to
45 degrees Celsius, and over a time period of 10 seconds to 30
minutes, e.g., 1 minute to 15 minutes, and using
2,4,6-trimethylbenzoyl-diphenylphospine oxide (TMDPO) as the
photoinitiator.
TABLE-US-00005 TABLE 5 Exemplary conductive hydrogel formulations.
Formulation* Water Content (%)** 1 HEMA/DMA 700CL 34 2 GMA/DMA
700CL NM 3 100% MAA/DMA 700CL 44 4 HEMA/GMA/DMA 700 CL 42 5 HEMA/
44 HEMA10/DMA 700 CL 6 HEMA/DMAC/DMA(700) 50 Crosslinker 7
HEMA/GMA/BDDA CL 41 8 HEMA10/HEMA/BDDA CL 39 9 HEMA/DMAC/DMA(700)
57 Crosslinker 10 NVP/DMAC/HEMA 50 11 NVP/DMAC/HEMA 69 12
NVP/DMAC/HEMA 78 13 NVP/DMAC/HEMA 77 14 NVP/DMAC/HEMA with glycerol
diluent 77 15 NVP/DMAC/HEMA 70 16 NVP/DMAC/HEMA with glycerol
diluent 78 17 HEMA/MEMA/PEG diluent 34 18 HEMA/MAA/DMA
700/water/PEG400 NM 19 HEMA/MAA/DMA 700/water/PEG400 20 *HEMA =
hydroxyethyl methacrylate; DMA = dimethylacrylamide; GMA = glycerol
monomethacrylate; MAA = methacrylic acid; DMAC = dimethylacetamide;
BDDA = 1,4-butanediol diacrylate; NVP = N-vinylpyrrolidone; MEMA =
methoxyethyl methacrylate; HEMA10 = poly ethoxy (10) ethyl
methacrylate. **NM = not measured.
[0089] Other exemplary conductive hydrogel formulations are
provided in Examples 1-7, and 15. Based on the data from
experiments run with these hydrogel formulations, a hydrogel that
exhibits high hydration with a minimal increase in mass and height
(i.e., swelling/expansion) may be useful. Expansion due to swelling
of the hydrogel generally produces effects that may require
balancing. For example, swelling enhances electrical conductivity,
makes the hydrogel more hydrophilic, and thus more comfortable when
in contact with skin, and reduces contact resistance. However, more
swelling also makes the hydrogel more sticky and less robust, and
therefore more prone to breakage during application of current, and
increases the drying out rate (although the amount of water left
over after a specific period of dry-out depends both on the rate of
dry out and the initial water content). Taking these effects into
consideration, exemplary formulations (e.g., formulations SB4A and
SB4B) may incorporate a diluent that is an inert solvent that forms
a hydrogel having a substantial swelling ratio (or water uptake)
but which does not expand upon hydration since the incoming water
replaces the diluent leaving with less volume change upon hydration
and swelling in water. For example, the hydrogel formulations
provided in Example 6 (hydrogel formulation SB4A) and Example 7
(hydrogel formulation SB4B) that include acrylic terminated
siloxane monomers may be useful. The SB4A and SB4B hydrogel
formulations demonstrated a high level of hydration with minimal
expansion, as shown in the data provided in Example 14. The
silicone hydrogel formulation provided in Example 15 (hydrogel
formulation SB5), which exhibited increased cross-linking due to
the inclusion of trimethoylol propane trimethacrylate, demonstrated
zero expansion, as shown in the data provided in Example 18.
Overall, the data provided in Examples 16-19 provide that the SB5
formulation (SB5) may be useful when formed as a hydrogel tip of a
nasal stimulator device. The expansion of the SB5 formulation upon
hydration was shown to be significantly less than earlier
formulations (e.g., SB1 and SB2), and extended less than 0.5 mm
beyond the boundary of the tip when the hydrogel was fully
hydrated. Additionally, resistance was less than 600.OMEGA., well
within requirements, and it did not increase beyond 1000.OMEGA.
upon drying for up to 8 hours. The results also showed that the SB5
formulation was sufficiently extracted and hydrated so as to be
ready for use after 12-24 hours of extraction in saline at 55
degrees Celsius. However, the hydrophobic nature of its surface
caused an increase in contact resistance, especially in contact
with parts of the nasal tissue that is especially hydrated. This
problem can likely be solved by a hydrophilic surface modification
or addition of a hydrating medium, as previously described herein.
A hydrogel that is capable of high levels of water uptake (i.e.,
high hydration) will typically be more electrically conductive.
Parameters such as monomer extraction rate and electrical
resistance can be measured and the resultant values used to
indicate the hydration level of the hydrogels, as provided in
Examples 8-12, 16, and 17. The addition of a diluent, as shown in
Example 9 does not appear to effect hydration of the hydrogel, but
may affect cure rate.
Manufacturing Methods
[0090] Various manufacturing methods are also described herein.
These processes may include various ways of curing the hydrogel
formulations, various ways of obtaining a suitable hydrogel shape,
and various ways of assembling the hydrogel at the tip of a nasal
stimulator. The manufacturing methods may be useful in forming the
hydrogel contact of the disposable pronged portion of the nasal
stimulator provided in FIG. 2, or hydrogel contacts of nasal
stimulator prongs/tips having alternative configurations, such as
the nasal stimulator prongs/tips described in U.S. application Ser.
No. 14/256,915 (U.S. Publication No. 2014/0316485), entitled,
"NASAL STIMULATION DEVICES AND METHODS," filed Apr. 18, 2014, the
contents of which were previously incorporated by reference in
their entirety (the conductive hydrogels in U.S. application Ser.
No. 14/256,915 are referred to as hydrogel electrodes). In general,
manufacturing methods that help with scalability and storage of the
shaped hydrogel may be useful. Furthermore, manufacturing methods
that increase the volume of hydrogel at the tip of the electrode of
a nasal stimulator may be beneficial since this would lead to less
drying out of the hydrogel. Manufacturing methods tailored so that
the hydrogel forms a bulge at the distal end of the electrode of a
nasal stimulator may also be useful.
[0091] In one variation of curing the hydrogel formulation,
disposable molds are used, e.g., as shown in FIG. 4. The disposable
molds form a continuous shell of the conductive hydrogel
formulation around the sleeve, while filling the space inside the
slot and the sleeve just next to the electrode. As noted in the
figure, the tube may be made from low cost biocompatible,
processable material that is transparent to UV radiation, e.g.,
polyethylene, polyvinylidene fluoride (PVDF), polypropylene (non-UV
absorbing grades), polystyrene, ABS and the like. The tube is
typically open at one end and closed at the other, and may have an
internal diameter of about 6.0 mm, a length of about 14 mm, and a
wall thickness ranging from about 0.20 to about 1.0 mm. Other
variations of the tube may have an internal diameter ranging from
about 3.0 to about 10 mm, and a length ranging from about 5.0 mm to
about 20 mm.
[0092] The disposable molds may be injection molded just in time
for use in the curing process. An exemplary assembly and curing
process, as shown in FIG. 5, may track to transport parts and
subassemblies, and robot to position them. In this process, the
electrodes, shaped as rods, springs or foils are assembled into the
sleeves that are injection molded separately. The preassembled
electrode and sleeve assembly may be inventoried and provided to
the final assembly process depicted in FIG. 5, or they may be
assembled on line, as shown in FIG. 5.
[0093] The conductive hydrogel formulations may be contained in
sealed containers that are opaque and isolated from air. The
formulations may also be de-aerated prior to being charged into the
container. In some variations, the disposable molds are injection
molded on line, and are stored in work in process inventory. Long
term storage of disposable molds is preferably avoided, since long
term storage would introduce dust particles into the molds, and
would then require the disposable molds to be washed or cleaned
prior to use. Next, the electrode subassembly is placed inside the
disposable mold and a specified volume of hydrogel formulation is
discharged into the disposable mold. The disposable mold is then
moved to a station in which radiation sources are placed in order
to provide uniform radiation on all sides of the disposable mold.
Temperature is controlled by flowing nitrogen through the station,
which also maintains the curing mixture in an oxygen free
environment. In this instance, the range of temperature of cure is
30-45 degrees Celsius and the cure times range from about 1 to
about 15 minutes. The subassembly is then removed from the
disposable mold and the disposable mold discarded after the cure is
complete.
[0094] In some variations, de-molding can be accomplished by
application of a rapid cooling pulse, e.g., by a brief immersion
into water at 0 degrees Celsius. The electrode subassembly
comprising a hydrogel shell may then be immersed in deionized water
for a period of 2-24 hours in order to remove unreacted monomers
and the diluent. The temperature of the deionized water may range
from about 35 to about 50 degrees Celsius or from about 10 to about
40 degrees Celsius. The electrode subassembly, also called the
disposable unit, is then removed from the water, briefly dried to
remove excess water, then packaged in a sealed pouch to be ready
for sterilization.
[0095] Alternative manufacturing methods for forming the hydrogel
into a suitable shape for use with a nasal stimulator device are
also described herein. Some variations of the method include a
dip-coating and spray technique. For example, the tip of a prong(s)
(800) of a nasal stimulator can be dipped up and down (in the
direction of the arrows) into the hydrogel (802) repeatedly, as
shown in FIG. 8A, or the prong(s) used to scoop the hydrogel (802)
at an angle, as shown in FIG. 8B. Here the viscosity of the
hydrogel can be adjusted so that the cavity (804) within the prong
(800) is filled with the hydrogel after dipping or scooping.
Additionally, a primer can be included in the hydrogel formulation
to help adhere the hydrogel to the prong when dipping or scooping.
The thickness of the hydrogel can be controlled by such factors as
the rate of ascent/descent of the prong during dipping or scooping,
temperature, and/or viscosity of the hydrogel. The viscosity of the
hydrogel may be adjusted to be high enough to allow for shape
memory before final curing. After dip-coating by either dipping or
scooping, curing of the hydrogel on the prong tip can be performed
using UV light (as described above) or by thermal methods. It is
understood that multiple dip/cure cycles can be implemented. Next,
one or more portions of the hydrogel tip can be masked so that an
insulation layer (806) can be applied, e.g., by spraying or
adhering, on the hydrogel tip (800) to cover and insulate those
portions of the tip (800) that are not intended to be conductive,
as shown in FIG. 8C. The insulation layer may comprise any suitable
insulator, e.g., a non-conductive polymer. After applying the
insulator, e.g., by spraying or adhering, the masked portion (808)
of the tip (800) would be conductive. Alternatively, when a mask is
not used, the orientation of the hydrogel tip can be controlled so
that only insulated areas are sprayed or exposed.
[0096] The hydrogel can also be shaped first and then placed at the
end of a conductor, e.g., the tip of a nasal stimulator prong.
Using such methods, the shaped hydrogel portion can be made ahead
of time and then hydrated in bulk, and/or cleared of excess diluent
and/or excess unreacted monomer in bulk, stored as a
hydrogel/conductor subassembly prior to hydration, or stored during
hydration (i.e., stored by leaving in a saline solution).
[0097] Shaping of the hydrogel can be accomplished in any suitable
fashion. In one variation, the hydrogel formulation is poured into
a tray and then conductors are placed in the formulation. The
formulation is then cured to form a hydrogel sheet and the sheet
shaped by cutting using a laser cutter, a die cutter, a blade, etc.
The cut hydrogel may be referred to as a hydrogel preform. If
desired, the cured hydrogel can also be shaped to include a bulge.
Alternatively, the hydrogel formulation can be poured into a tray
including individual molds or cavities having a desired shape,
e.g., a bulge. The hydrogel shape formed by the individual molds or
cavities may also be referred to as a hydrogel preform. In some
instances, cutting and molding may be used in combination in a
manner where the hydrogel is cut into a molded preform.
[0098] More specifically, and as shown in FIGS. 9A-9I, the hydrogel
mixture (1) is first poured into a tray (2). As shown in FIG. 9B,
tray (2) can be configured to include individual molds or cavities
(3) into which the hydrogel (1) is poured. Conductors (4) may then
be placed inside the hydrogel (1) prior to curing. The conductors
may have any suitable form and be made from any suitable conductive
material. For example, and as depicted in FIG. 9C, the conductors
may be configured as a metallic strip (5) with holes (7), a coil
spring (6), or a wire that is bent/shaped, e.g., into a loop (8),
etc. These conductor configurations may be useful for creating a
mechanical lock between the hydrogel and the conductor. In some
instances the metallic strip (5) is configured without holes.
[0099] Placement of the conductors into the hydrogel formulation
can include the use of locating or capturing features. The locating
and capturing features can also help with insertion of the
conductors to a desired depth into the hydrogel. For example, as
shown in FIG. 9D, an end of conductor (4) can be placed on the tray
with the help of a locating feature configured as a peg (9) or a
well (10). The end of conductor (4) can also be placed with the
help of a capturing feature such as plate (11), which is provided
above the tray (2), as depicted in FIG. 9E. In such instances,
plate (11) may be configured to capture conductors based on their
geometry, e.g., the conductor may have a larger section (12) at one
of its ends, have a bent/deformed section (13), or have a clamping
or interference fit (14) with plate (11). After the conductors have
been placed into the hydrogel, the hydrogel is cured according to
any one of the methods described herein. When the hydrogel has been
molded/cured into a sheet, the hydrogel can thereafter be formed
into a desired shape, e.g., by a laser cutter, a die cutter, a
blade, etc. The component created by shaping (element 16 in FIG.
9G), either by cutting or molding, may be referred to as a
conductor-hydrogel subassembly (element 17 in FIG. 9G).
[0100] As shown in FIG. 9G, the conductor-hydrogel subassembly (17)
can be subsequently hydrated and stored in an aqueous environment
until used for further assembly of the tip of a nasal stimulator
device, or it may be stored dry for later processing. According to
one variation, as shown in FIG. 9H, assembly of the
conductor-hydrogel subassembly (17) into a molded part (20) to
create the desired final tip assembly can include dropping the
subassembly (17) into a hollow shaft (21) of the molded part (20)
such that the hydrogel (16) rests on a stepped section (22) inside
the shaft (21). Here the conductor (4) may be bent/deformed at the
location where it exits the shaft (21), e.g., to create a
mechanical lock between the subassembly (17) and the molded part
(20). Referring to FIG. 9I, a cap (24) may also be included as part
of the molded part (20) by, e.g., a hinge-like mechanism (23).
[0101] The hydrogel can also be incorporated into the nasal
stimulator device tip by controlled dispensing of the hydrogel
formulation, e.g., by computer numerical control (CNC) or robotics,
or by hand, directly into a cavity of the tip assembly. Controlled
dispensing can be accomplished by tilting mechanisms to ensure
vertical alignment of the window, or the use of guides, but is not
limited thereto. It is understood that other suitable controlled
dispensing processes can be employed. A controlled dispensing
method may be useful in controlling the size of the bulge of the
hydrogel tip.
[0102] In one variation, tilting during the dispensing process may
be useful in controlling the introduction of hydrogel into the
device tip. For example, as shown in FIG. 10A, the tip portion (25)
can be tilted during dispensing of the hydrogel formulation (26)
from a dispenser device (28). The amount of tilting may vary, and
can range from about 5 to about 45 degrees. The amount of tilt may
be dictated by the geometry of the window being filled. In general,
the nasal stimulator device will be tilted so that walls of the
window are equidistant about a vertical centerline of the opening,
thereby allowing gravity to equally disperse the liquid hydrogel
formulation. For example, if the centerline of the window being
filled is 45 degrees from the centerline, the nasal stimulator
device is tilted (rotated) 45 degrees. Tilting may generally be
accomplished using tilting mechanisms such as pins, rollers, and/or
plates, etc. FIG. 10B illustrates how a displacement roller (27)
can be used to tilt tip portion (25) after the hydrogel formulation
has been dispensed and cured. After dispensing the hydrogel
formulation into one tip of tip portion (25), the formulation is
cured and the displacement roller (27) moved to tilt the tip
portion (25) in the opposite direction. The tilting mechanisms
generally tilt fixtures (e.g., flat surfaces such as plates) upon
which the tip portions have been placed to expose each cavity to
the dispenser since the cavity faces inwards on normal orientation
(when the tip portion is placed on the fixture), and for dispensing
the opening in the tip portions should face the upward direction.
In some instances, the fixture may also have alignment pins that
complement holes provided in the base portion of the nasal
stimulator.
[0103] One or several of the tip portions may be tilted during the
dispensing process. For example, as shown in FIG. 10C, hydrogel
dispenser (28) includes multiple dispenser tips (29) and multiple
tip portions (25) disposed on plate (30). Slides (not shown)
coupled to multiple rollers (31) are used to tilt the multiple tip
portions (25). The plate (30) can also be moved back and forth in
the direction of the arrows to achieve a rocking/tilting
motion.
[0104] In another variation, one or more guides disposed in or on a
part of the tip portion may function to control dispensing of the
hydrogel by enabling tilting or flexing of the tip portion such
that the cavity is substantially perpendicular to the hydrogel
dispenser. The guides may be rails and/or slots/slits that
interface with a corresponding structure or geometry on a fixture
to reversibly attach the tip portion to the fixture and tilt or
flex the tip portion so that the cavity can be filled. For example,
as shown in FIGS. 11A-11C, an inner slot (32) may be provided in
the tip portion (33) (FIG. 11A), a rail or slit (34) may be
provided within a lumen (35) of the tip portion (33) or on the
outside surface (36) of the tip portion (33) (FIG. 11B), or a slot
(37) may be provided in the tip (38) of the tip portion (33)
similar to a lock and key combination (FIG. 11C).
[0105] In yet a further variation, the hydrogel of the tip portion
can be shaped using a casting process. Here the hydrogel
formulation is poured into a mold containing a hollow cavity of the
desired shape, and then allowed to solidify. Some variations of the
mold may be configured as shown in FIG. 12A. Referring to the
figure, mold (39) includes a base block (44), rocker plates (42),
screws (43), and compression springs (45). The base block (44)
includes one or more casting surfaces (41) configured to form a
bulge in the hydrogel tip (i.e., a bulge casting surface). The
bulge casting surface will typically have the same radius as a
distal end of the tip portion (see element 48 in FIG. 12B), and
includes a recess such as recess (40) for creating a bulge during
casting. Rocker plates (42) compress and secure the tip portions
(see FIG. 12 C) to the base block (44) using screws (43) and
compression springs (45). The rocker plates may be made from a
material that transmits UV light, e.g., an acrylic material. The
height of the screws (43) may be adjusted to control the amount of
compression imparted by plate (42). More specifically, as shown in
FIGS. 12B-12D, the manufacture of a hydrogel tip by casting may
include providing a pronged disposable tip (46) with windows (47),
and orienting the distal ends (48) such that the windows (47) face
the casting surface (41) of the base block (44) of mold (39) (FIG.
12B). The distal ends (48) of the pronged tip (46) are then secured
to the base block (44) by tightening of screws (43) so that rocker
plates (42) are compressed against the base block (44) (FIG. 12 C).
Again, the tips (46) are loaded into the mold with the windows
facing the casting surface. A UV curable hydrogel formulation as
described herein can then be injected through a channel (49) in the
disposable tip (46) that is fluidly connected to the distal ends
(48) in a manner that delivers hydrogel to the windows and the
casting surface (FIG. 12C). As stated above, the casting surface
includes a recess for forming a bulge in the hydrogel. After the
hydrogel formulation is injected into the tip portion (46), UV
light can be applied to cure the hydrogel. Either the rocker plates
or base block can be made from a material that transmits UV light.
An exemplary UV transmissive material comprises glass. Here the UV
light is capable of being transmitted through the base block (44)
and distal end (48). The rocker plates (42) are then released so
that the distal ends (48) can be removed from the base block (44).
As shown in FIG. 12D, the resulting hydrogel formed by the casting
process has a bulge (50) that protrudes from window (47). Although
a single mold is shown in FIGS. 12A-12D, it is understood that a
ganged array of molds could be configured and employed for large
scale production.
[0106] Some methods of manufacturing include decreasing the wall
thickness at the end of the tip portions so that the volume of
hydrogel can be increased in the tip portions. In one variation,
this is accomplished by molding the tip from a single component and
using a micro-molding process and material. Using this process, for
example, the wall thickness of the tip portion can be decreased
from thickness A (shown between the arrows on the left) to
thickness B (shown between the arrows on the right) in FIG. 13 to
thereby increase the volume within the tip end. Other methods may
include steps that create a high volume to surface area ratio to
maintain the desired level of hydration of the hydrogel.
Tip Assembly Methods
[0107] Methods for assembling the tip portion of a nasal stimulator
device are further described herein. These assembly methods may be
mixed and matched with the various ways of shaping the hydrogel, as
described above. The methods may also be used to assemble the
disposable tip portion shown in FIG. 2, or tip portions having
other configurations. Some variations of the tip portion may
require only partial assembly before the hydrogel is added to them.
In general, the assembly methods include steps that fix the
hydrogel within the tip portion, either mechanically (e.g., by
hydrating after placing the hydrogel into the tip, interference
fit, screw fit, etc.), or chemically (e.g., by epoxy, bioadhesives,
ultrasound, etc.).
[0108] In variations where the hydrogel formulation is dispensed
into the window of the tip portion, the tip may include an
electrode (51) having a distal end (59) that is insert molded into
a cap (52) and a flexible, frangible, or spring-like proximal end
(60) comprising arms (61), as shown in FIG. 14A. The electrode (51)
may include a slot (53) that functions to provide mechanical
retention of the hydrogel within the cavity (element 54 in FIG.
14B) of a tip assembly (element 55 in FIG. 14B). In its partially
assembled state, as provided in FIG. 14B, the hydrogel can be
injected using a dispensing system and method as described above,
into cavity (54) through window (56). Here formation of the
hydrogel bulge may be controlled by the surface tension and/or the
viscosity of the uncured hydrogel.
[0109] After curing of the hydrogel, the tip assembly may be
attached to a nasal stimulator device as depicted in FIG. 14C.
Referring to FIG. 14C, the tip assembly (55) is attached to the
rest of the disposable tip portion via a retainer block (57) at the
distal end of a flex tube (58) (within the prong of a stimulator
device) that has a tip retainer (62b) with a ramp surface (62). The
electrode (51) of the tip assembly (55) is pushed in the direction
of the arrow so that it is forced to follow the ramp surface (62).
The flexible/frangible nature of the electrode arms (61) allow them
to snap back to their original configuration when fully inserted to
substantially surround the tip retainer (62b). The electrode arms
(61) may be configured to permanently deform when pulled upward in
the direction of the arrow and detached from the tip retainer (62b)
so that the tip assembly cannot be reused, as shown in FIG. 14
D.
[0110] In variations where the hydrogel is preformed using, e.g.,
any of the methods described above, the hydrogel may be preformed
as a cylinder (63) having a slot (64) for accepting an electrode
(65), as shown in FIG. 15A. Here the hydrogel is an unhydrated
preform that is hydrated after the tip assembly is fully assembled.
It is understood that the hydrogel preform may or may not be washed
of excess unreacted monomer prior to integration into the tip
assembly. During the hydration process, the hydrogel preform (63)
will generally swell in the direction of the arrows, fill open
spaces, and expand through window (66) to create a stimulation
(contact) surface (67). Furthermore, given that the clearance
between the electrode (65) and slot (64) is small, the electrode is
typically fully contacted by the hydrogel in the initial phase of
hydration (e.g., upon 20% hydration). This is a beneficial safety
feature since it ensures that when a patient uses the nasal
stimulator device, the full surface of the electrode is carrying
the electrical current. An angular slot (68) on the exterior of the
tip assembly opposite the window (66) can be used to align and mate
the tip assembly to a corresponding structure in a dispensing
cassette during the manufacturing process, as further described
below.
[0111] In other variations, a hydrogel preform may be placed into a
tip assembly that includes a hinge, e.g., a living hinge. For
example, as shown in FIG. 16A, the tip assembly (69) may be
configured to include a first side (70) having a cavity (77a) for
placement of the hydrogel preform (not shown), a window (71) that
allows the hydrogel preform to expand, a channel (72) for slidable
engagement of an electrode (not shown), and a hole (73). First side
(70) is coupled to a second side (74) via a living hinge (75). The
second side (74) includes a cavity (77b), a tapered boss (76) that
is accepted by the hole (73) when the second side (74) is folded
over to contact the first side (70) at living hinge (75). The
tapered boss (76) and hole (73) have an interference fit and may be
welded together prior to hydration of the hydrogel preform. In
another example, the tip assembly may include a deflectable
electrode (78) capable of being deflected in the direction of the
arrow to allow a hydrogel preform (79) to be installed in the tip
assembly, as shown in FIG. 16B. Here the electrode includes a hole
(73) for acceptance of the tapered boss (76) when the first (70)
and second (74) sides are rotated at the living hinge (75) to close
the sides together. Instead of a tapered boss and hole, the sides
may also be secured together using a tongue and groove
configuration. For example, as shown in FIG. 16C, a female tapered
groove (80) can be configured to have an interference fit with a
male tapered tongue (81). Other variations of the tip assembly are
shown in FIG. 16D, and include a hydrogel retention bar (82) to
help secure the hydrogel within the tip and/or a living hinge (84)
recessed within a slot (83) provided in the surface of the tip to
help prevent abrasion of nasal tissue.
[0112] The manufacturing methods may also employ the use of a
dispensing cassette to assemble the tip assemblies in bulk. Bulk
packaging may reduce the amount of packaging materials and volume,
which is convenient for the end user. An exemplary dispensing
cassette is provided in FIGS. 17A-17F. Referring to FIG. 17A, the
dispensing cassette (90) may include a cassette housing (85) having
a proximal end (86) and a distal end (87), and an alignment block
(88) coupled to the proximal end (86), and a constant force spring
(89). A plurality of tip assemblies (91) can be stored in the
cassette housing (85) and held in place by the constant force
spring (89), which pushes the tips (91) against the alignment block
(88). A plurality of holes (93) are provided in the constant force
spring (89), which are spaced apart a distance equal to the length
of one tip assembly (91). When the dispensing cassette (90) is at
rest, a pin (92) of the alignment block (88) is not engaged with a
hole (93) in the constant force spring (89). As provided in more
detail in FIG. 17B, when the dispensing cassette is at rest, a
spring (94) in its unrestrained state pushes pin (92) out of hole
(93) in the constant force spring (89), and the constant force
spring (89) pushes the tips (91) (see FIG. 17A) back toward surface
(95) of alignment block (88). When the dispensing cassette is
activated by the user for the attachment of the tips (91) to the
rest of the nasal stimulator device (not shown) as depicted in FIG.
17C, the alignment block (88) is depressed to compress spring (94)
and allow engagement of pin (92) with constant force spring hole
(93) to release the load provided by constant force spring (89)
against the tips (91) while a tip is being attached. A wick (96)
can also be provided to keep a supply of moisture in the dispensing
cassette so that the hydrogel in the tips (91) do not dry out
prematurely. The wick (96) may be saturated with a fluid such as
saline. As previously described, the tip assemblies may include a
slot (97) (as shown in FIG. 17D) configured to engage a
complementary structure of the cassette housing (99) so that
angular alignment of the electrodes can be controlled. For example,
as depicted in FIG. 17E, the slots (97) in the tips (91) engage
ribs (98) of the cassette housing (99).
[0113] Some variations of the manufacturing method combine the
electrode and tip retainer shown in FIG. 14C with the dispensing
cassette described in FIGS. 17A-17C, as illustrated in FIGS.
18A-18D. First, the alignment block (88) is depressed in the
direction of the arrow (FIG. 18A) to expose a new tip assembly (91)
that can be accessed by the pronged portion (101) of the nasal
stimulator device (103) (FIG. 18B). The electrode (105) is aligned
to attach to a connector (not shown) in the prong (101). Next, the
device (103) and prongs (101) are advanced through the access holes
(107) in the alignment block (88) until a tip (not shown) is
attached as described in FIG. 14C. After attachment, the device
(103) may be withdrawn from the alignment block (88) and
compression force on the alignment block (88) may be released in
the direction of the arrow, as shown in FIG. 18D.
[0114] If tip detachment is desired, a tip removal tool may be
employed, as depicted in FIGS. 19A-19C. Referring to FIG. 19A, tip
assemblies (91) can be inserted into a cavity (111) of tip removal
tool (113) that resembles a clasp. The removal tool (113) can then
be pinched to compress the tip assemblies (91) within the removal
tool (113), as shown in FIG. 19B. While maintaining the compression
force, the device (103) can be pulled away from the tip removal
tool (113) to detach the device (103) from the tip assemblies (91),
as shown in FIG. 19C.
[0115] In yet further variations, the manufacturing methods include
steps that attach a flexible base unit to a rigid tip assembly. For
example, as shown in FIG. 20A, caps (115) on hydrogel preforms
(117) may be provided. Rigid, elongate electrodes (119) may extend
from the caps (115) for advancement through a flexible base (121).
Segments (123) including windows (125) are attached to the flexible
base (121). As shown in the figure, segments (123) have an open top
(127) so that the hydrogel preforms (117) can be loaded therein.
After the electrodes (119) are advanced into the flexible base
(121) the caps (115) can be fixed to the flexible base, e.g., by
welding. In another example, as shown in FIG. 20B, the flexible
base (121) is configured to include tapered ends (129) that accept
complementary structures (131) near the distal end (133) of
elongate electrodes (119).
Methods of Use
[0116] Methods for stimulating nasal or sinus tissue (and the
lacrimal gland) are also described herein. In one variation, the
method includes placing an arm of a nasal stimulator device against
a nasal or a sinus tissue, the arm having a distal end and an
electrically conductive hydrogel disposed at the distal end; and
activating the nasal stimulator device to provide electrical
stimulation to the nasal or the sinus tissue, where the
electrically conductive hydrogel is used to facilitate an
electrical connection between the nasal stimulator device and the
nasal or the sinus tissue. As stated above, the conductive hydrogel
may comprise a first monomer; a second monomer; and a
photoinitiator, where the first monomer is an acrylate monomer and
the electrically conductive hydrogel has one or more
characteristics that adapt it for use with a nasal stimulator
device. The conductive hydrogel may include monomers, diluents,
photoinitiators, and other components as described herein, e.g.,
the components provided in Table 1 and Table 3. Again, the
formulations are subjected to UV radiation to form a cross-linked,
conductive hydrogel. The conductive hydrogels used in these methods
may include those listed in Tables 2 and 5.
[0117] Generally, when one or more nasal or sinus afferents
(trigeminal afferents as opposed to olfactory afferents) are
stimulated, a lacrimation response is activated via a naso-lacrimal
reflex. This stimulation may be used to treat various forms of dry
eye, including (but not limited to), chronic dry eye, episodic dry
eye, seasonal dry eye. To provide continuous relief of dry eye
symptoms, nasolacrimal stimulation from one to five times a day may
be needed. In some instances, the stimulation may be used as a
prophylactic measure to treat users which may be at an increased
risk of developing dry eye, such as patients who have undergone
ocular surgery such as laser vision correction and cataract
surgery. In other instances, the stimulation may be used to treat
ocular allergies. For example, an increase in tear production may
flush out allergens and other inflammatory mediators from the eyes.
In some instances, the stimulation may be configured to cause
habitation of the neural pathways that are activated during an
allergic response (e.g., by delivering a stimulation signal
continuously over an extended period of time). This may result in
reflex habitation which may suppress the response that a user would
normally have to allergens.
EXAMPLES
[0118] The following examples further illustrate the conductive
hydrogel formulations as disclosed herein, and should not be
construed in any way as limiting their scope.
Example 1: Method of Making an Electrically Conductive Hydrogel for
Use with a Nasal Stimulator Device
[0119] In a round bottom flask wrapped in aluminum foil and
provided with a magnetic stirrer, introduce a first monomer, a
second monomer, and a photoinitiator. Additional monomers (e.g., a
third or fourth type of monomer, etc.) and/or a diluent may also be
added. Clamp the flask on top of a magnetic stirrer/heater that is
fitted with a nitrogen purge line. After turning on the magnetic
stirrer and nitrogen purge, mix the contents of the flask for five
minutes to form a monomer mixture. While the monomers are being
mixed, insert sleeves of a nasal device (e.g., sleeve (300) shown
in FIGS. 3A-3C) into disposable molds (e.g., as shown in FIG. 4)
having windows or louvers that open to let in UV light. The sleeves
should be oriented vertically within the molds. Next, draw the
monomer mixture from the flask into a syringe and cover the syringe
with foil. Attach a needle, e.g., a 30 gauge blunt needle, to the
syringe. Insert the needle into the sleeve and fill the sleeve with
the monomer mixture. Next, open the louvers and irradiate the molds
for about three minutes with UV light. Thereafter, turn the molds
horizontally with the louvers facing upward and irradiate the molds
for about seven minutes with UV light. Cool the molds before
removing the sleeves from them.
Example 2: Preparation of a Silicone Hydrogel Including
Methacryloxypropyl Tris (Trimethoxysiloxy) Silane and Methanol
Diluent
[0120] In a round bottom flask wrapped in aluminum foil and
provided with a magnetic stirrer, the following was added:
EGMDA (Ethylene glycol dimethacyrlate) (0.081 g) NVP (N-vinyl
pyrollidone) (2.179 g) GMA (Glyceryl monomethacrylate) (1.112 g)
DMA (Dimethyl acrylamide) (3.917 g) Methacryloxypropyl tris
(trimethyoxysiloxy) silane (2.712 g)
Lucirin (TPO) (0.081 g)
Methanol (2.88 g)
[0121] The flask was clamped on top of a magnetic stirrer/heater
that was fitted with a nitrogen purge line. The contents of the
flask were then mixed for five minutes to form a monomer mixture.
While the monomers were being mixed, the nasal device sleeves and
disposable molds were prepared as described in Example 1. The
monomer mixture was then drawn into a syringe, injected into the
sleeves, and irradiated as described in Example 1. The molds were
cooled before removing the sleeves from them.
Example 3: Silicone Hydrogel SB1
[0122] Silicone hydrogel formulation SB1 was prepared and molded
into sleeves as described in Example 1. The components of the SB1
hydrogel are provided below. A diluent was not included in the SB1
hydrogel formulation.
TABLE-US-00006 SB1 14020 (for kinetic study (formulated on
03/13/14) molecular molar ratio weight mole 10 gram to major
Monomers (g/gmole) mole mass (g) fraction batch (g) monomer wt %
HEMA 130.14 0.0708 10.0000 0.0964 0.9000 0.2152 9.5299 EGOMA 198.00
0.0018 0.3500 0.0022 0.0336 0.0049 0.3335 NVP 111.14 0.2969 33.0000
0.3725 3.1700 0.8315 31.4487 DMA 99.13 0.3571 35.4000 0.4481 3.4006
1.0000 33.7359 allyl methacrylate 126.16 0.0028 0.3500 0.0035
0.0336 0.0078 0.3335 methacryloxypopyl 422.82 0.0591 25.0000 0.0742
2.4015 0.1656 23.8248 trisTrimethoxysiloxy siiane lucerin 348.00
0.0024 0.8320 0.0030 0.0800 0.0067 0.7937 Total 0.7969 104.9320
1.0000 10.0800 100.0000
Example 4: Silicone Hydrogel SB2
[0123] Silicone hydrogel SB2 was prepared as in Example 1. The
components of the SB2 hydrogel are provided below. A methanol
diluent was included in the SB2 hydrogel formulation.
TABLE-US-00007 SB2 14021 (for kinetic study (formulated on
03/13/14) molecular molar ratio weight mole 10 gram to major
Monomers (g/gmole) mole mass (g) fraction batch (g) monomer wt %
HEMA 130.14 0.0768 10.0000 0.0443 0.9606 0.2152 7.4582 EGDMA 198.00
0.0018 0.3500 0.0010 0.0336 0.0040 0.2610 NVP 111.14 0.2969 33.0000
0.1714 3.1700 0.8315 24.6120 DMA 90.13 0.3571 35.4000 0.2061 3.4006
1.0000 26.4020 allyl methacrylate 126.16 0.0028 0.3500 0.0016
0.0336 0.0078 0.2610 methacryloxypropyl 422.82 0.0591 25.0000
0.0341 2.4015 0.1656 18.6455 trisTrimethoxysiloxy silane lucerin
348.00 0.0024 0.8320 0.0014 0.0800 0.0067 0.6211 diluent methanol
32.04 0.9357 29.9808 0.5401 2.88 2.6203 22.3602 Total diluent +
hydrogel 1.7327 134.128 1.0000 12.88 100.0000
Example 5: Silicone Hydrogel SB3
[0124] Silicone hydrogel SB3 was prepared and molded into sleeves
as in Example 1. The components of the SB3 hydrogel are provided
below. The SB3 hydrogel formulation included a methanol diluent and
the HEMA monomers were replaced with EGDMA monomers, which are more
hydrophilic than the HEMA monomers.
TABLE-US-00008 SB3 (Kinetic Study 3) 10 gram molecular hydrogel
molar ratio to weight mole batch major Wt Monomers (g/gmole)
fraction (g) monomer Fraction EGDMA 198.00 0.0025 0.081 0.0103
0.0062 NVP 111.14 0.1203 2.179 0.4963 0.1681 GMA 160.00 0.0426
1.112 0.1759 0.0858 DMA 99.13 0.2424 3.917 1.0000 0.3022
(3-methacryloyloxypropyl) 422.82 0.0393 2.712 0.1623 0.2092
tris(trimethylsiloxy) silane lucerin 348.00 0.0014 0.080 0.0058
0.0062 Diluent methanol 32.04 0.5514 2.88 2.2751 0.2222 Total
1.0000 12.9600 1.0000
Example 6: Silicone Hydrogel SB4A
[0125] Silicone hydrogel SB4A was prepared and molded into sleeves
as in Example 1. The components of the SB4A hydrogel are provided
below. The SB4A hydrogel formulation included a methanol diluent
and two different acrylic terminated siloxane monomers.
TABLE-US-00009 SB4A (Kinetic Study 3) 10 gram molecular hydrogel
molar ratio to weight mole batch major wt Monomers (g/gmole)
fraction (g) monomer fraction Trimethylol 338.00 0.0019 0.131
0.0103 0.0091 propane trimethacrylate NVP 111.14 0.0908 2.074
0.4963 0.1440 GMA 160.00 0.0322 1.058 0.1759 0.0735 DMA 99.13
0.1830 3.727 1.0000 0.2588 (3-methacryloyloxypropyl) 422.82 0.0347
3.010 0.1894 0.2091 tris(trimethylsiloxy) silane lucerin 348.00
0.0011 0.080 0.0001 0.0056 diluent methanol 32.04 0.6563 4.32
3.5863 0.3000 Total Diluent + hydrogel 1.0000 14.400 1.0000
Example 7: Silicone Hydrogel SB4B
[0126] Silicone hydrogel SB4B was prepared and molded into sleeves
as in Example 1. The components of the SB4B hydrogel are provided
below. The SB4 hydrogel formulation also included a methanol
diluent and two different acrylic terminated siloxane monomers.
TABLE-US-00010 SB4B (Kinetic Study 3) 10 gram molecular hydrogel
molar ratio to weight mole batch major wt. Monomers (g/gmole)
fraction (g) monomer fraction Trimethylol 338.00 0.0019 0.137
0.0103 0.0095 propane trimethacrylate NVP 111.14 0.0939 2.167
0.4963 0.1505 GMA 160.00 0.0333 1.106 0.1759 0.0768 DMA 99.13
0.1893 3.894 1.0000 0.2704 (3-methacryloyloxypropyl) 422.82 0.0307
2.696 0.1023 0.1872 tris(trimethylsiloxy) silane lucerin 348.00
0.0011 0.080 0.0059 0.0056 Diluent methanol 32.04 0.6497 4.32
3.4321 0.3000 Total 1.0000 14.4000 1.0000
Example 8: Measurement of Hydration of the SB1 Hydrogel as a
Function of Monomer Extraction Rate
[0127] After curing, the hydration of the SB1 hydrogel formulation
was measured as a function of the extraction rate of unreacted DMA
and NVP monomers, as shown below. The formulation was immersed in
saline (NaCl in deionized water, 0.9% w/w) using 3.5 mL of saline
per sleeve containing approximately 60 mg of polymer per sleeve.
The temperature was held constant at 55.degree. C., and the
solution was shaken in the incubated shaker at 100 rpm. Extraction
was carried out for 1, 2, 3, 4, 6, 8, 12 and 24 hours, with the
saline extractant being replaced with fresh saline solution after
each period. The extraction process removes unreacted impurities
from the polymer and also allows it to undergo hydration.
Electrical resistance is believed to be dependent on the level of
hydration of the polymer.
[0128] The extracts were analyzed by GC-MS chromatography, on an
Agilent 7890A GC with Agilent 5975C mass selective quadrupole
detector, monitoring N-vinyl pyrrolidone (NVP), Dimethyl acrylamide
(DMA). Total ion chromatograms were recorded on each elute, and
peaks identified using pure NVP, DMA and methanol as
references.
[0129] After about one hour of extraction (the terms extraction and
hydration are used interchanageably in this application), the
extraction rate for the SB1 hydrogel formulation was about 170
.mu.g/hr for DMA (shown in FIG. 21A) and about 450 .mu.g/hr for NVP
(shown in FIG. 21B).
Example 9: Measurement of Hydration of the SB2 Hydrogel as a
Function of Monomer Extraction Rate
[0130] After curing, the hydration of the SB2 hydrogel formulation
was measured as a function of the extraction rate of unreacted NVP
monomers, as shown in FIG. 22A and as described in Example 8, and
as a function of the extraction rate of methanol, as shown in FIG.
22B. About one hour after curing, the extraction rate for the SB2
hydrogel formulation was about 1,150 .mu.g/hr for NVP, which was
much higher than that obtained with the SB1 hydrogel formulation.
As noted above, a difference between the SB1 and SB2 formulations
is that SB2 contained a methanol diluent. The presence of the
diluent substantially accelerated the extraction of unreacted
monomers from SB2, as shown by the relative rates of extraction of
NVP from SB2 and SB1 (1,150 .mu.g/hr vs. 450 .mu.g/hr. However, the
presence of the diluent also lowered the cure rate of SB2 relative
to SB1, by reducing the effective mole fractions of each of the
monomers (data not shown).
Example 10: Measurement of Hydration of the SB1 and SB2 Hydrogels
as a Function of Electrical Resistance
[0131] After curing, the hydration of the SB1 and SB2 hydrogel
formulations were measured as a function of electrical resistance
over a 72 hour extraction period (monomer extraction is a process
that helps complete hydration of the hydrogel). Electrical
resistance was measured by a multimeter set to read in serial
resistance mode. One multimeter lead makes contact with the spring
of the reference sleeve and the other with the spring of the test
sleeve. The resistance measurement was read within 30 seconds. The
resistance of the circuit, i.e., resistance other than the test
sleeve, was estimated to be 2k.OMEGA.. "Sleeve resistance," as
referred to in the Examples, means resistance values specific to
the sleeve, i.e., with the 2k.OMEGA. removed.
[0132] From the data provided in FIGS. 23A and 23B, it is shown
that for both hydrogel formulations, the electrical resistance is
high (approximately 145 to 175 k.OMEGA.) after the first hour of
hydration/extraction, but as the hydrogel becomes more hydrated,
the resistance drops (i.e., they become more conductive). The data
is not plotted after 8 hours of hydration given the very low
values.
Example 11: Measurement of Hydration of the SB2 and SB3 Hydrogels
as a Function of Electrical Resistance
[0133] After curing, the hydration of the SB2 and SB3 hydrogel
formulations were measured as a function of electrical resistance
over a period of one to 8 hours and a period of four to 72 hours,
as described in Example 10. The data provided in FIGS. 24A and 24B
show that hydration continues over a long period (here 72 hours).
These hydrogels were still usable after 8 hours of hydration (they
were still conductive). Furthermore, the gel mass of SB3 is
significantly higher than that of SB2 after hydration. It should be
noted that although the gel mass of SB3 is higher than that of SB2,
gel height is lower for SB3. This is due to the presence of the
diluent.
Example 12: Measurement of Hydration of the SB4A and SB4B Hydrogels
as a Function of Electrical Resistance
[0134] After curing, the hydration of the SB4A and SB4B hydrogel
formulations were measured as a function of electrical resistance
over a period of 144 hours. The data provided in FIG. 25 also shows
that the hydrogels remain hydrated over a long period of time, and
become more conductive as hydration increases.
Example 13: SB2 and SB3 Hydrogel Expansion Due to Hydration
[0135] Mass and height for the SB2 and SB3 hydrogel casts were
measured to determine swelling of the hydrogels as a function of
hydration. The measurements are provided in FIGS. 26A and 26B.
Replacement of HEMA monomers with EGDMA monomers in SB3 rendered it
more hydrophilic, which resulted in an increase in water uptake
relative to SB2, and thus, a larger mass.
Example 14: SB4A and SB4B Hydrogel Expansion Due to Hydration
[0136] Mass and height for the SB4A and SB4B hydrogels were
measured and compared to that of the SB3 hydrogel to determine
swelling of the hydrogels as a function of hydration, as shown in
FIGS. 27A and 27B. The SB4A and SB4B hydrogels, which exhibited
high hydration (see Example 12) expanded less than the more
hydrophilic SB3 hydrogel. Thus, with the SB4A and SB4B hydrogels,
higher conductance was achieved with less swelling/expansion.
Example 15: Silicone Hydrogel SB5
[0137] Silicone hydrogel formulation SB5 was prepared and molded
into sleeves as described in Example 1. The components of the SB5
hydrogel are provided below. A methanol diluent was included in the
SB5 hydrogel formulation.
TABLE-US-00011 SB5 10 gram molar ratio molecular hydrogel to weight
mole batch major wt. Monomers (g/gmole) fraction (g) monomer
fraction Trimethylol 338.00 0.0021 0.119 0.0151 0.01186 propane
trimethacrylate NVP 111.14 0.0686 1.278 0.4957 0.12779 GMA 160.00
0.0243 0.653 0.1760 0.06530 DMA 99.13 0.1383 2.299 1.0000 0.22992
(3-methacryloyloxypropyl) 422.82 0.0224 1.591 0.1623 0.15914
tris(trimethylsiloxy) silane lucerin 348.00 0.0011 0.067 0.0082
0.00666 Diluent methanol 32.04 0.7431 3.993 5.3738 0.39934 Total
1.0000 10.0000 1.0000
[0138] In the SB5 formulation, the UV initiator, diphenyl
(2,4,6-trimethylbenzoyl)phosphine oxide (CAS #75980 60-8, Lucirin
TPO), was selected since it is capable of being activated by UV
radiation in the wavelength range of 400-450 nm, a band that is
transmitted by the sleeve material (Versaflex OM3060-1, a
styrene-ethylene/butylene-styrene copolymer). Addition of
trimethylol propane trimethacrylate enhanced cross-link density and
rendered the mixture more resistant to dry out.
Example 16: Measurement of Hydration of the SB5 Hydrogel as a
Function of Monomer Extraction
[0139] After curing, the hydration of the SB5 hydrogel was measured
as a function of the extraction rate of unreacted DMA and NVP
monomers, and methanol, as shown in FIGS. 28A-28C, and as similarly
described in Example 8. Briefly, the extracts were analyzed by
GC-MS chromatography, on an Agilent 7890A GC with Agilent 5975C
mass selective quadrupole detector, monitoring N-vinyl pyrrolidone
(NVP), Dimethyl acrylamide (DMA), and methanol (MeOH). Total ion
chromatograms were recorded on each elute, and peaks identified
using pure NVP, DMA, and methanol as references. The data in the
graphs provided in FIGS. 28A-28C show that the rate of extraction
of methanol is fastest followed by that of DMA. Extraction of NVP
is the slowest. The extraction rate depends solely on the
solubility of each species in saline at the temperature of
hydration (55 degrees Celsius), since the swelling of the hydrogel
network is the same in all cases. As provided in the graphs, the
extraction rates of all species appear to reach a low plateau after
24 hours of hydration. Based on these results, it was concluded
that the SB5 hydrogel was ready to use after 24 hours of
hydration.
Example 17: Measurement of Hydration of the SB5 Hydrogel as a
Function of Electrical Resistance
[0140] After curing, the hydration of the SB5 hydrogel formulation
was measured as a function of electrical resistance over different
periods of extraction, similar to that described in Examples 10-12.
As shown in FIG. 29, the electrical resistance dropped
significantly upon hydration caused by extraction with saline. The
electrical resistance of the SB5 hydrogel reached a level of
greater than 0.6 k.OMEGA. after 12 hours of extraction, and a lower
plateau after approximately 24 hours of extraction.
Example 18: SB5 Hydrogel Expansion Due to Hydration
[0141] Mass and height (expansion) for the SB5 hydrogel casts were
measured to determine swelling of the hydrogels as a function of
hydration (and extraction period). Referring to the data table in
FIG. 30A, at 48 hours, the hydration percentage (defined as
100*(M.sub.48 hours-M.sub.0 hours)/M48 hours, where M is mass in
grams) of SB5 (42-05) is calculated to be about 35.5%, which was
significantly less than that of SB1 (42-01) and SB2 (42-02). The
reduced hydration percentage may be attributed to the increased
crosslink density and increased hydrophobicity of SB5 relative to
SB1 and SB2. Thus, benefits of the SB5 hydrogel may be that it is
capable of achieving a level of electrical conductivity sufficient
to perform its electrical function while also having a relatively
low level of hydration, and that its processability is improved.
The increased cross-link density also appeared to raise the glass
transition temperature of the unhydrated hydrogel network (data not
shown). These changes in the composition of the SB5 hydrogel
relative to the SB1 and SB2 hydrogels may improve its drying out
time and its robustness to shear forces induced by rubbing against
nasal tissue.
[0142] Referring to the Gel Mass vs. Hydration Duration graph
provided in FIG. 30B, the SB5 hydrogel reached a threshold of
hydration at about 24 hours of extraction, in contrast to the SB1
and SB2 hydrogels in which hydration continued to increase gel mass
until about 72 hours (see, e.g., SB2 data in Example 13). This is
consistent with the lower hydration percentage of SB5.
[0143] Provided in FIG. 30C is a Gel Expansion vs. Hydration
Duration graph, which shows the data obtained from recording the
increase in height of the SB5 hydrogel obtained from optical photos
of hydrated sleeves. The data indicated that gel height reached a
plateau after about 24 hours of extraction, in contrast to the SB1
and SB2 hydrogels, which continued to show increases in gel height
up to and beyond 72 hours of extraction by saline under identical
conditions (see, e.g., SB2 data in Example 13).
[0144] Overall, the data for the SB5 hydrogel showed that its
equilibrium water content was about 35%. Referring to Example 15,
the amount of methanol (diluent) used in this formulation is about
39.9%. These values indicate that the SB5 hydrogel is a zero
expansion hydrogel. The data provided on gel height expansion
showed an increase from 5.0 mm (measured prior to hydration) to 5.2
mm (after completion of hydration at about 24 hours), which
indicates that an increase in about 4% is attributable to
additional complexation of water molecules by the polymeric network
relative to methanol.
Example 19: Contact Angle of the Silicone SB5 Hydrogel
Formulation
[0145] The contact angle of the SB5 hydrogel used as an electrical
contact at the tip of a nasal stimulator device was measured by
placing 1 .mu.l of deionized water on its surface, then
photographing the drop using a Leica M-80 microscope having a L80
nmnm digital camera, and having the LAS version 4.3.0 optical
capture software. The contact angle was estimated from the
photograph. The measurement was repeated using an electrical
contact tip that had been hydrated by immersion into deionized
water for 30 minutes just prior to measurement. The contact angle
was measured to be 90 degrees in both cases. These results indicate
that the surface of SB5 is hydrophobic, even though the overall gel
mass is highly hydrophilic. Thus, the SB5 hydrogel appears to have
a complex polymer morphology comprised of a hydrophilic core and a
hydrophobic surface, e.g., as shown in FIG. 7.
Example 20: Biocompatibility of the SB5 Hydrogel Formulation
[0146] MEM studies were performed on SB5 hydrogel samples hydrated
in saline for 12 and 24 hours at 55 degrees Celsius to determine
the biocompatibility of the hydrogel, as shown below. The studies
were completed by Acta Laboratories, Inc., in accordance with USP
36/NF 31 Supplement 2, (87) Biological Activity Tests, InVitro,
Elution Test.
TABLE-US-00012 KS5 14043 12 hrs Elution Results % % Round
Intracytoplasmic Confluent and Loosely % Cell Culture Granules
Monolayer Attached Lysis Grade Reactivity Sample #1 100 (+) 0 0 0
None Sample #2 100 (+) 0 0 0 None Reagent Control #1 100 (+) 0 0 0
None Reagent Control #2 100 (+) 0 0 0 None Negative Control #1 100
(+) 0 0 0 None Negative Control #2 100 (+) 0 0 0 None Positive
Control #1 0 (-) 0 100 4 Severe Positive Control #2 0 (-) 0 100 4
Severe
TABLE-US-00013 KS5 14043 24 hrs Elution Results % % Round
Intracytoplasmic Confluent and Loosely % Cell Culture Granules
Monolayer Attached Lysis Grade Reactivity Sample #1 100 (+) 0 0 0
None Sample #2 100 (+) 0 0 0 None Reagent Control #1 100 (+) 0 0 0
None Reagent Control #2 100 (+) 0 0 0 None Negative Control #1 100
(+) 0 0 0 None Negative Control #2 100 (+) 0 0 0 None Positive
Control #1 0 (-) 0 100 4 Severe Positive Control #2 0 (-) 0 100 4
Severe
* * * * *